Little progress has been achieved in the past 30 years in the treatment of liver diseases as compared with treatment of diseases in other therapeutic fields. The reasons for this lagging are to be looked for both in the polymorphous character of liver diseases and in some principles applied so far in therapeutics.
The problem of liver therapeutics is a concern of long standing with clinicists, who have suggested the use of liver extracts as far back as the beginning of the twentieth century. See Gilbert, A. and Carnot, P., Note preliminaire sur l'opotherapie hepatique, Compt. rend. Soc. Biol., Aca. Sci. Paris, 48, 937 (1896). This therapy was practiced in the first half of this century. See Buettner, H. E., Experimentelle und klinische Untersuchungen uber die Wirkung einspritzbarer Leberextrakte, Fortschr. Therap., 11, 257-346 (Berlin 1935). Liver extracts or hydrolysates were prepared industrially, but they were not biologically standardized as to their liver-protecting effect. In the end it was agreed to determine the vitamin B.sub.12 contents in these preparations, and considering the biological role of the vitamin to take it as a measure of their activity.
The outstanding progress of biochemistry in the last decades has shown a better understanding of the essential metabolic links in liver cell functioning. Attempts were made as a result to introduce certain components of these metabolic processes in the treatment of liver diseases. Products suggested for therapeutic use include mixtures of amino acids, purine and pyrimidine compounds, phospholipids, orotic acid, vitamins and sugars. The preparations are marketed under various pharmaceutical trade names such as Hapesteril, Essentiale, Purinor, Hepatofalk, Aspatofort, among others. Clinical results obtained with these preparations are limited. They are active only in the steady stage of liver disease and ineffective in the evolutive stage. The restricted effect of these preparations is due to the fact that they do not take into consideration a basic element in liver disease, namely, that they are in the first place determined by primary cell membrane damage. See Popper, H., The Problem of the Hepatitis, Amer. J. Gastroenterology, 4, v. 55, 335-346 (New York, 1971) and Popper, H., Membrane Alterations as Basis of Liver Injury, Falk Symposium, 22 (Basel, 1976). The passage through cell membranes in metabolic processes requires an active membrane transport, sometimes by means of a "carrier" substance, as in the case of aspartic and glutamic acids. The presence of this carrier in the membrane implies the morpho-functional integrity of the membrane, but this integrity is deficient in the course of liver diseases. As a result, the components of the various metabolic processes occurring in the liver, administered in the form of pharmaceutical preparations, fail to be integrated in the metabolic processes of the hepatocyte for lack of a carrier in the structure of the membrane. This is the limiting factor for the clinical efficacy of glutamic and aspartic acids in evolutive liver diseases.
Immunological studies in the last decade have proved that the mesenchyma is also involved in the membrane damage process by a mechanism of self-aggression. This finding has determined the introduction of certain steroids and immunosuppressives in therapeutical practice. Among the first structures to be used for this purpose are the corticosteroids, which have proved their effectiveness in severe clinical forms of both acute viral hepatitis and chronic aggressive hepatitis. However, in the course of the long term clinical use of these structures it becomes obvious that this pharmacotherapy was far from rational. See Sherlock, S. H., Chronic Hepatitis and its Therapy, Lecture Xth European Congress of Gastroenterology (Budapest, 1976) and Cook, G. C. et al, Controlled Prospective Trial of Corticosteroid Therapy in Active Chronic Hepatitis, Quart. J. Med., 40, 150-166 (London, 1971). It is shown in these references that in acute viral hepatitis, steroid therapy is the starting point for the development of liver cirrhosis in the subsequent evolution of patients so treated. For lack of a more adequate therapy, in chronic, aggressive hepatitis, the treatment with steroids and immunosuppressives is still used.
Under the circumstances it appeared necessary to reconsider the fundamental principles of the pharmacotherapy to be applied in liver diseases. Hence experimental pharmacological studies were conducted to elucidate the liver-spleen interrelation in respect to metabolic loading with various drugs. Since drugs may be considered as "foreign bodies" for the metabolic processes of the reticulo-endothelial system (RES), it must be assumed that many of the processes concerning the metabolism and elimination of the drugs are connected with the RES structures located in the liver and spleen. It is a well-known fact that the acetylation of sulphonamides is supported to the extent of 80% by Kupffer cells, and that the acetylation of bacterial toxines is achieved in RES dependent cell structures, resulting in the emergence of sulphonamide side-effects. See Govier, W. C. Role of Kupffer Cells in Acetylation, J. Pharmac. Exp. Therapy, 150, 305-310, (New York, 1965) and Freedman, H. M. et al Dissociation of Antitoxic and Immunogenic Activities of Endotoxine by Acetylation, Ann. N.Y. Acad. Sci. 2, v. 133663-667 (New York, 1966). The competition of two metabolic acetylations of the same cellular level is the reason for the side-effects of sulphonamides. If sulphonamides are administered for therapeutic purposes unless the RES dependent acetylation is concentrated on the bacterial toxines, a part of this metabolic process will be located in the spleen. Timar, M. et al, Studies on Acetylation of Sulphamethoxypyrimidine in Endotoxine Tolerant Mice, Biochem. Pharmacol., 21, Pergamon Press, 42-422 (Oxford, 1972). This example demonstrates that the molecular biology of the liver is first of all connected with the RES dependent cell structures, which are located in the liver and spleen. See Timar, M., Liver-Spleen Relationship in the Study of Liver Protecting Drugs, Advances in Experimental Medicine and Biology, 73 A, 455-457 (New York, 1976) and Timar, M., The Extrapolation of Liver Functionality Data From the Animal to the Human in the Treatment of the Acute Stage of Liver Damage with FH, II Farmaco, ed. prat. No. 9, 473-478.
As already mentioned, steroid treated patients suffering from acute viral hepatitis will in some cases develop cirrhosis in their future clinical condition. Studies performed for the explanation of this side-effect of steroid therapy have highlighted the fact that during the regenerative processes in the liver, a leucine-containing peptide structure is secreted in the spleen. See Timar, M., Cortisone Damaging Effect in Experimental Mitochondrial Liver Injury, X.sup.th European Congress of Allergy and Immunology, Proceedings, 360364 (Prague, 1977). The peptide is involved in the protein synthesis processes in the liver. Its secretion occurs by a positive feedback mechanism between the liver and the spleen. The secretion of this peptide is inhibited by steroid therapy as well as by heliotropine, an alkaloid which is involved in the aetio-pathogeny of liver cirrhosis in the endemic area of Central Asia.
These experimental findings provided the baseline for research aimed at developing a new drug for the treatment of liver diseases which should preserve the trophic functions of the spleen. A complex peptide structure was discovered as a result. It is a component of the cell membranes of liver and is known as the liver-protecting factor (HF).